Application of Zr-MOFs based copper complex in synthesis of pyrazolo[3, 4-b]pyridine-5-carbonitriles via anomeric-based oxidation

In this research article, Zr-MOFs based copper complex as a novel heterogeneous and porous catalyst was designed and prepared. The structure of catalyst has verified by various techniques such as FT-IR, XRD, SEM, N2 adsorption–desorption isotherms (BET), EDS, SEM-elemental mapping, TG and DTG analysis. UiO-66-NH2/TCT/2-amino-Py@Cu(OAc)2 was used as an efficient catalyst in the synthesis of pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives. The aromatization of titled molecules is performed via a cooperative vinylogous anomeric-based oxidation both under air and inert atmospheres. The unique properties of the presented method are short reaction time, high yield, reusability of catalyst, synthesis of desired product under mild and green condition.

Nowadays, metal-organic frameworks as high surface areas materials are a new group of porous materials with potential applications such as gas storage and separation, drug delivery, sensors, batteries, supercapacitors as well as catalytic applications 1,2 . This framework is a class of organic-inorganic hybrid crystalline materials consisting of metallic nucleus that are linked by strong coordination bonds to organic ligands 3,4 . The different properties of these porous materials make them a good catalytic candidate for cross coupling, oxidation/reduction, and multicomponent reactions [5][6][7][8][9][10] . The post-modification method enhances catalytic performance and their variability. According this method, our research team reported a number of catalysts in the synthesis of organic compounds as biological active candidates [11][12][13][14][15][16] . Copper complex is widely used as catalysts in many organic reactions such as oxidation, cross coupling and catalytic organic reactions [17][18][19] . Recently, multicomponent reactions have investigated in the presence of palladium, nickel, copper, Fe, and Zr based catalytic systems [20][21][22] . In this report, a porous and heterogeneous catalyst based on Zr-MOFs with a copper complex is prepared. The simultaneous presence of copper and zirconium will enhance the catalytic application. This new system of porous complexes will lead to a new approach in the design and synthesis of catalysts. Figure 1 shows the final structure of the copper complex based on Zr-MOFs as well as the topology and structure of the UiO-66(Zr) grid.
Anomeric effect (AE) as a fundamental example of stereoelectronic interactions has great educational and research applications [33][34][35] . It was discovered in 1955 by J. T. Edward in his studies on the carbohydrate chemistry 36 . The reported theory for the development of anomeric effect (AE) concept had been proposed that sharing the lone pair's electrons of heteroatoms (X: N, O) to the anti-bonding orbital C-Y (n X → σ * C-Y ) weakened it (Fig. 3a).  Stereoelectronic effects have also a major role in the oxidation-reduction of susceptible biological compounds such as NADPH/NADP + (Fig. 3b) [37][38][39] . Recently, we and our coworkers have reviewed the role of the abovementioned fundamental concepts comprehensively 34,35 .

Results and discussion
Since the role of the anomeric effect can be found in the course of synthesis of various organic compounds 53,54 , herein, we decided to synthesize new compounds via an anomeric supporting mechanism. On the other hand, the importance of developing new catalysts for chemical reactions increased our motivation to produce new porous catalysts. Creating a copper complex based on metal-organic frameworks creates a new approach to the preparation of heterogeneous catalysts. The structure of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 as a porous and heterogeneous catalyst was completely identified using various techniques such as FT-IR, XRD, SEM, N 2 adsorption-desorption isotherms (BET), BJH, EDS, SEM-elemental mapping, TG and DTG. The UiO-66-NH 2 / TCT/2-amino-Py@Cu(OAc) 2 was used for prepareing new pyrazolo [3,4-b]pyridine-5-carbonitriles. These compounds may be had biological and medicinal applications due to the presence of indole and pyrazole moieties. The structure of the synthesized compounds was confirmed using FT-IR, 1 H-NMR, 13 C-NMR and melting point   www.nature.com/scientificreports/ The FT-IR spectra of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 as a catalyst and starting materials were shown in Fig. 6. The two peaks at 3475 and 3357 cm −1 of NH 2 functional groups are represented synthesis of UiO-66-NH 2 45 . Also, the absorption peaks at 2800-3000 cm −1 are related to aromatic C-H and C=C stretches bands. The addition of different compounds during the catalyst synthesis steps results in changes in the spectra that indicate a change in structure.
The XRD pattern of different stages of materials and catalyst synthesis was compared (Fig. 7). The XRD pattern of UiO-66-NH 2 was identical to the previously reported data 45 . The last stage of copper complex based on Zr-MOFs has been proved by appearing of peaks. Also, below the peak at 2θ < 10, indicating the structure of the crystal plates of the various phases has suitable stability.
The morphology of UiO-66-NH 2 and UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 was also studied by scanning electron microscopy (SEM) technique (Fig. 8a). As shown in Fig. 8a, morphology of catalyst particles is tetrahedral which is in good condition and not completely stacked. Also, the morphology of UiO-66-NH 2 is stable after post-modification. Elemental mapping analysis shows Zr, N, O, C and Cu atoms which were confirmed in the structure of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 (Fig. 8b). Furthermore, the well-dispersed distribution of elements in the UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 was determined and verified by elemental mapping analysis (Fig. 8b). www.nature.com/scientificreports/ In another searching, the textural properties of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 were studied by N 2 adsorption-desorption isotherms (Fig. 9a). Based on the obtained results, the area calculated based on the BET equation, the total pore volume 115 m 2 g −1 and 0.1523 cm 3 g −1 respectively. The pore size distribution of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 based on BJH method is shown in (Fig. 9a). The mean pore diameter for the catalyst is 8.48 nm. The presence of a suitable surface area, as well as the size of catalyst cavities can be a major reason for the high efficiency at the synthesis of pyrazolo [3,4-b]pyridine-5-carbonitriles. The thermal gravimetric (TG) and derivative thermal gravimetric (DTG) analysis of UiO-66-NH 2 /TCT/2-amino-Py@ Cu(OAc) 2 was shown in Fig. 9b. According to this diagram, several failures due to the separation of the copper complex and organic compounds of Zr-MOFs are shown. The diagram shows that the synthesized catalyst is stable up to 240 °C.
Suggested mechanism for the synthesis of pyrazolo [3,4-b]pyridine-5-carbonitriles using UiO-66-NH 2 / TCT/2-amino-Py@Cu(OAc) 2 as a heterogeneous and porous catalyst was shown in Fig. 11. At the first step, ethyl cyanoacetate is converted to enolate form and react with activated aldehyde to produce intermediate (I) by losing one molecule of H 2 O. In the following, (3-(1H-indol-3-yl)-1-phenyl-1H-pyrazol-5-amine (1) and/ or 3-(4-chlorophenyl)-1H-pyrazol-5-amine (2) attack to intermediate (I) as a Michael acceptor created intermediate (II). In the next step, intermediate (II) is converted to intermediate (III) through tautomerization and intramolecular cyclization. Finally, the intermediate (III) converts to their corresponding derivatives via a cooperative vinylogous anomeric based oxidation and releases one molecule of hydrogen (-H 2 ) and/or hydrogen peroxide (-H 2 O 2 ) molecules 26,60,61 . The obtained results of the reaction model under argon, nitrogen and oxygen atmospheres are similar which are verified the presented mechanism. The term cooperative is used when more than one lone pair of electrons and other donors are sharing the anti-bonding orbitals of one acceptor bond (n N → σ * C-H ). The simultaneous cooperative sharing of electrons from donors into the anti-bonding orbitals of the C-H bond is a major driving force for hydride releasing (n N → σ * C-X ). To prove the recyclability of the presented catalyst, we tested model reaction under the optimal reaction conditions in the previously section. The results of Fig. 12a show that the UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 as a catalyst can be reused up to 4 times without noticeable changes in its catalytic activity. This performance indicates the high stability of the copper complex created on the Zr-MOFs as a heterogeneous and porous catalyst. To prove the stability of the catalyst structure, the recovered catalyst was evaluated by FT-IR and XRD analysis. The results are shown in Fig. 12b and c. According to the results, there have been not many changes in the catalyst structure, indicating the stability of the catalyst. Also, to investigate the heterogeneous nature of the protocols and Cu leaching, ICP results proved that no Zr and Cu leaching was detected in the filtrate (Zr: 2.41 × 10 −6 and Cu: 2.03 × 10 −5 mol/g respectively) upon reaction completion, which indicates the high stability of the prepared catalyst.

Conclusions
In summary, Zr-MOFs based copper complex was introduced. At this catalyst, copper was supported on the surface of metal-organic frameworks as a new porous complex. Proper stability and morphology of the presented catalyst can create a new approach in the preparation of porous and heterogeneous catalysts. Catalytic performance of UiO-66-NH 2 /TCT/2-amino-Py@Cu(OAc) 2 was demonstrated in the synthesis of new pyrazolo [3,4b]pyridine-5-carbonitriles via anomeric based oxidation concept. These compounds can have biological and medicinal applications due to the presence of indole and pyrazole nucleus. High efficiency of products and gentle green conditions are other features of the products synthesized using this new porous and heterogeneous catalyst.

Data availability
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.